WO1999015129A2 - SELECTIVE cPLA2 INHIBITORS - Google Patents

SELECTIVE cPLA2 INHIBITORS Download PDF

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Publication number
WO1999015129A2
WO1999015129A2 PCT/US1998/019426 US9819426W WO9915129A2 WO 1999015129 A2 WO1999015129 A2 WO 1999015129A2 US 9819426 W US9819426 W US 9819426W WO 9915129 A2 WO9915129 A2 WO 9915129A2
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
hydrogen
alkylamino
substituted
Prior art date
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PCT/US1998/019426
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English (en)
French (fr)
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WO1999015129A3 (en
Inventor
Jacques Banville
Yonghua Gai
Graham Johnson
Fred Christopher Zusi
James R. Burke
Original Assignee
Bristol-Myers Squibb Company
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Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU93954/98A priority Critical patent/AU730364B2/en
Priority to CA002304503A priority patent/CA2304503A1/en
Priority to EP98947093A priority patent/EP1140791A2/de
Publication of WO1999015129A2 publication Critical patent/WO1999015129A2/en
Publication of WO1999015129A3 publication Critical patent/WO1999015129A3/en

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    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines

Definitions

  • Inflammatory diseases of the skin such as psoriasis and atopic dermatitis, afflict greater than 5% of the population.
  • the treatment of these disorders typically involves the use of topical steroids.
  • these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy.
  • topical application of a drug is difficult for many patients where the affected area may be very large.
  • Phospholipase A 2 is the common name for phosphatide 2- acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids.
  • the fatty acid is arachidonic acid
  • further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma.
  • Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
  • PLA 2 enzymes exist as secreted forms (MW ⁇ 12,000-15,000) and cytosolic forms (MW ⁇ 85,000).
  • the cytosolic or cPLA 2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
  • Inappropriate activation of the cytosolic PLA 2 enzymes can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke. 1996, 27, 527-535), Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke. 1996, 3, 51-63 and see also U.S. Patent 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation. 1994, 3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham et al, American Tournal of Physiology. 1996, 270; Cell Physiology 39:0037-0050) and macrophage activation (Balsinde et al, Tournal of Biological Chemistry. 1996, 271, 6758- 6765).
  • Selective inhibitors of the cPLA 2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases.
  • the literature describes a significant number of compounds said to be phospholipase A 2 inhibitors, but few selective inhibitors for the cPLA 2 enzymes are available. The present inventors had as their goal the synthesis of novel compounds which would be selective and potent inhibitors of the cPLA 2 enzymes.
  • selective inhibitors of the cPLA 2 enzymes means that the inhibitors inhibit the cPLA 2 enzymes with a potency 20-fold or greater than they inhibit the lower molecular weight synovial PLA 2 enzymes.
  • R is either H or OH.
  • JP09268153A discloses cPLA 2 inhibitors of the formula RCOCF 3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid.
  • the compounds are said to be useful as antiinflammatory or antiallergic drugs.
  • B represents a non-aromatic C 3 -C 8 carbocycle, a C 3 -C 8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C ⁇ -C 4 alkyl group, a C j -C 4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
  • X is a member selected from the group consisting of a halogen atom, — S— aryl,— S— heterocycle, and — P0 R 2 wherein each R is independently selected from the group consisting of a hydrogen atom and C j -C j alkyl;
  • R 1 and R 2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: -(CH 2 ) q -A' wherein q is an integer of 2 to 4, and A' is a member selected from the group consisting of a hydroxyl group, a group represented by the formula:
  • R 5 and R 6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: ⁇
  • R 7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula:
  • s is an integer of 2 to 5;
  • R 1 and R 2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula:
  • g and h are each an integer of 1 to 4, and B' stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or R 1 and R 2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R 1 and R 2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
  • R 3 represents a hydrogen atom, a lower alkyl group, or a C 3 -C 8 cycloalkyl group
  • R 4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom
  • n is an integer of 1 to 4, provided that when n is 2, the two R 4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A 2 activity, particularly cPLA 2 .
  • U.S. Patent 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA 2 enzymes, but it is not indicated whether these compounds are selective for the cytosolic enzymes or even whether they inhibit the cytosolic enzymes. These compounds have the generic formula
  • R 1 is selected from
  • R 1 and R 5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
  • R 2 and R 3 are each independently selected from 2 (a) hydrogen,
  • R 5 is as defined above or is selected from
  • R 6 is selected from
  • R 8 , R 9 and R 14 are each independently selected from
  • R 10 , R 15 , R 16 and R 17 are each independently selected from
  • R 11 is selected from
  • R 13 is perfluoro ⁇ alkyl
  • a and B are each independently
  • X 1 is selected from
  • n 0, 1, 2, 3 or 4;
  • n 2, 3, 4, 5, 6 or 7;
  • r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • the present invention is directed to selective cytosolic PLA 2 inhibitor compounds of the formula
  • R 1 is (C ⁇ -C6)alkyl, (C2-C6)alkenyl, (C 2 -C 6 )alkynyl, (C ⁇ -C6)alkoxy,
  • R 2 preferably 1-3, of (C C 6 )alkyl, -COO-(C C 6 )alkyl, — c — - R 3 in which R 2 and R 3 are as defined above, halo, hydroxy, -0-(C 1 -C 6 )alkyl, -S-(C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl;
  • p 0, 1 or 2;
  • A is V-(R c ) n -;
  • R c is a straight or branched chain alkyl group
  • V is O, -S-, -SO-, -S0 2 , -CONH or NHCO when n is an integer of from 1 to 6 or V is (C 2 -C 6 ) alkenyl or a bond when n is 0 or an integer of from 1 to 6;
  • D is -(CH2)m or a bond linking the 1 ⁇ ring to Y;
  • n is an integer of from 1 to 6;
  • Y is -O-, -S-, -SO-, -S ⁇ 2; - — or a bond;
  • R 4 is as defined below for R 7 ;
  • X is S or O
  • q is an integer from 1 to 6;
  • R is hydrogen or ( -C ⁇ alkyl;
  • R is hydrogen, CN, NO2, OH, -0-(C ⁇ -C6)alkyl, (C1-C6) alkyl, phenyl or (Cl-C6)alkylphenyl;
  • R and R 6 are each independently hydrogen or ( - g) alkyl
  • R 7 and R 8 are each independently;
  • R 15 is hydrogen or (C r C 6 ) alkyl, or o R 2 - C- N-R 3 in which R 2 and R 3 are as defined above, ( -C alkyl or (C j -C 6 ) alkyl substituted by one or more, preferably
  • phenyl or heterocyclic groups said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C,-C 6 ) alkoxy, 1-3 ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C 6 ) alkylthio, amino, 1-3
  • R 16 and R 17 are each independently (C ⁇ -Ci ⁇ )alkyl or (C2-Ci8)alkenyl or (C ⁇ -Ci8)alkyl or (C2-Ci8)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Ci-C6)alkoxy, l-3(C ⁇ -C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, l-3(Ci-C6)alkylamino, o R 2 1-3 di(C ⁇ -C6)alkylamino, C0 2 H, 1-3 -COO(C ⁇ -C6)alkyl, -C-N- R 3
  • R and R are as defined above for R and R except that they may
  • R 18 19 not be hydrogen, or R and R taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R 7 and R 11 are as defined above, or R 18 , R 19 and R 11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by
  • R 13 is (C ⁇ -C ⁇ s)alkyl or (C ⁇ -Cis)alkyl substituted by carboxy
  • R 2 and R 3 are as defined above, hydroxy, -0-(C C 6 ) alkyl, -0-(C C 6 ) alkyl or -S-(C C 6 ) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (C C 6 ) alkoxy, (C x -C 6 ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( - ) alkylthio, amino, ( - ) alkylamino, di(C,-C 6 ) alkylamino, C0 2 H, COO-(C,-C 6 ) alkyl, S0 3 H, o R 2 S0 2
  • R 2 and R 3 are as defined above;
  • r is 0 or an integer of from 1 to 3;
  • R 7 is as defined above;
  • M is -(CH2-) m T where T is — C— , — C-O , -c-N— , i n which R 2 is as defined above, -S0 2 - or a bond when MR 7 is on nitrogen and providing
  • R 14 is hydrogen or (Cl-C ⁇ )alkyl
  • n 0 or an integer of 1-6;
  • R 7 cannot be hydrogen
  • R 18 and R 19 are phenyl or phenyl substituted by
  • Also provided by this invention are methods for inhibiting cytosolic PLA 2 in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I and methods for using the compounds of formula I to treat various diseases characterized by inappropriate activation of the cytosolic PLA 2 enzymes such as asthma, allergic rhinitis, cerebral ischemia, Alzheimer's Disease, rheumatoid arthritis, acute pancreatitis, inflammatory bowel disease, psoriasis, gout, neutrophil and platelet activation, chronic skin inflammation, shock, trauma-induced inflammation such as spinal cord injury, damage to the skin resulting from UV light or burns and macrophage activation.
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier and processes for preparing the compounds of formula I.
  • the object of this invention was to discover a selective cPLA 2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA 2 enzymes.
  • a selective cPLA 2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA 2 enzymes.
  • a selective cPLA 2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA 2 enzymes.
  • such compound would also be devoid of undesirable lipid-perturbing activities associated with skin irritation.
  • C M8 alkyl refers to straight and branched chain alkyl groups with 1 to 18 carbon atoms.
  • C 2 -C 18 alkenyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon double bond.
  • C 2 -C 18 alkynyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon triple bond.
  • halogen or halo as used herein refers to fluorine, chlorine, bromine or iodine.
  • Aryl as used herein refers to a C 6 monocyclic aromatic ring system or a C 9 or C 10 bicyclic carbocyclic ring system having one or two aromatic rings such as phenyl or naphthyl.
  • substituted aryl refers to aryl groups substituted with one or more (preferably from 1 to 3) substituents independently selected from (C j -C 6 )alkyl, haloalkyl, ( -C alkoxy, (C j -C alkoxy-carbonyl, ( -C alkanoyl, hydroxy, halo, mercapto, nitro, amino, cyano, ( -C alkylamino, di(C C 6 )alkylamino, carboxy, aryl, aryl (C 1 -C 6 )alkyl, aryl (C 1 -C 6 )alkoxy, heterocyclic, heterocyclic ( -C alkyl and the like.
  • heterocyclic refers to a 4-, 5- or 6- membered ring containing one, two or three heteroatoms selected from N, O and S.
  • the 5-membered ring has 0-2 double bonds and the 6- membered ring has 0-3 double bonds.
  • the nitrogen heteroatoms can be optionally quaternized or N-oxidized.
  • the sulfur heteroatoms can be optionally S-oxidized.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring.
  • Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyr
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
  • the invention also includes pharmaceutically acceptable salts of the compounds of formula I.
  • a compound of the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups. Accordingly, a compound may react with any of a number of inorganic bases, and organic and inorganic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of formula I which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene-sulfonate, phenylacetate, phenylpropionate,
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • Suitable organic bases include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1- ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N- ethylpiperidine, benzylamine, dicyclohexylamine, or the like pharmaceutically acceptable amines.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • the present invention also includes solvated forms of the compounds of formula I, particularly hydrates, in which the trifluoromethyl ketone group exists as a mixture of ketonic I and hydrated forms ⁇ and are each independently interconvertible and pharmacologically active.
  • the present invention also includes prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic unsubstituted or substituted 0,0-ketals, 0,S-ketals, 0,N-ketals or S,N- ketals such as cyclic cysteamyl derivatives, cyclic glycolates, thioglycolates, glyoxylates or oxalates, and the like. It also includes trifluoromethylalcohols obtained by chemical reduction of trifluoromethylketones. Such forms are physiologically hydrolyzable groups which are converted in vivo to a pharmacologically active compound of formula I or II, or a crystalline form of such compounds, see scheme below.
  • prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic
  • R alkyl or substituted alkyl
  • R ⁇ / R Preferred compounds of formula I are those where the -A-CCF 3 substituent is linked to the phenyl ring at the para or meta position, most preferably at the para position.
  • 11 Preferred embodiments of the compounds of general formula I include
  • R 1 is benzyl; p is 0, 1 or 2; A is V-(CH 2 ) n -; V is
  • X is S or O
  • q is an integer of from 1 to 6;
  • R 9 is hydrogen or ( -C alkyl
  • R 10 is hydrogen, CN, N0 2 , OH, -0-(C r C 6 ) alkyl, (C,-C 6 ) alkyl, phenyl or (C r C 6 ) alkylphenyl;
  • R 5 and R 6 are each independently hydrogen or ( - ) alkyl; and R 7 and R 8 are each independently a) hydrogen; b ) ( -C 18 ) alkyl; c) (C ⁇ -C 18 ) alkyl substituted by one or more of, preferably 1-3,
  • R 15 is hydrogen or (C r C 6 ) alkyl
  • heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
  • R 2 hydrogen or (C C 6 ) alkyl, or - c- N- R 3 in which R 2 and R 3 are each independently hydrogen or ( -C 6 ) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
  • R 16 and R 17 are each independently (C ⁇ -C ⁇ s)alkyl or (C2-Ci8)alkenyl or (C ⁇ -C ⁇ s)alkyl or (C2-C ⁇ )alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C ⁇ -C6)alkoxy, l-3(C ⁇ -C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C ⁇ -C6)alkylthio, amino, 1-3
  • R 2 alkyl or - c- N- R 3 in which R 2 and R 3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • R 7 cannot be hydrogen
  • R 13 is (C ⁇ -C ⁇ 8)alkyl or (C ⁇ -C ⁇ s)alkyl substituted by carboxy, o II O II R I 2 _ _ -c-o-(c r c 12 ) alkyl, - C- N-R 3 in which R and R are as defined above, hydroxy, -0-(C r C 6 ) alkyl, -0-(C C 6 ) alkyl or -S-(C C 6 ) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), (C ⁇ -C 6 ) alkoxy, ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C j -C 6 ) alkylthio, amino, (C C 6 ) alkylamino, di(C ⁇ -C 6
  • R 2 - c- N- R 3 in which R 2 and R 3 are as defined above; r is 0 or an integer of from 1 to 3;
  • R 7 is as defined above;
  • M is -(CH2-)mT where T is — C— , - C- O , - c - N— , m which R 2 is as defined above, -S0 2 - or a bond when MR 7 is on nitrogen and providing O
  • O O R 14 is -C— , -C-O— , -O-, -S-, -SO-, -S ⁇ 2-, -N— or a bond when MR 7 is on a carbon atom of the heterocyclic ring;
  • R is hydrogen or (Cl-C6)alkyl
  • n 0 or an integer of 1-6;
  • R 7 where R 7 is as defined above, providing that when Y is -SO- or -S0 2 -, R 7 cannot be hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • Another preferred embodiment comprises a compound of the formula
  • n is 0 or an integer of from 1 to 6, the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring and Z is
  • R 1 is benzyl; p is 0, 1 or 2; n is 0 or an integer of from 1 to 6; the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring; and Z is il
  • q is an integer of from 1 to 6;
  • X is S or O
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • substituent -(CH 2 ) n COCF 3 is in the para position of the phenyl ring, R 5 and R 6 are both hydrogen, q is 1, 2 or 3, n is 2 or 3, B 1 is
  • R 7 and R 8 are each
  • Another preferred embodiment comprises a compound of the formula 3i
  • n is 0 or an integer of from 1 to 6; the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring; and Z is
  • R 13 , r, M and R 7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • n is 0 or an integer of from 1 to 6, the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring; and Z is
  • R 5 and R 6 are each independently hydrogen or (C ⁇ -C ⁇ 8)alkyl; and Q and R 7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • n is 0 or an integer of from 1 to 6;
  • heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
  • R 15 is hydrogen or ( - ) alkyl, or - c- N- R 3 in which
  • R 2 and R 3 are as defined above, ( -C 6 ) alkyl or ( -C 6 ) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3
  • R 2 and R 3 are each independently hydrogen or ( -C 6 ) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
  • R 16 and R 17 are each independently (Ci-C ⁇ s)alkyl or (C2-C ⁇ s)alkenyl or (C ⁇ -Cis)alkyl or (C2-C ⁇ )alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3
  • R 9 is hydrogen or (C ⁇ -C6)alkyl and R 2 and R 3 are as defined above; and R 18 and R 19 are phenyl or phenyl substituted by
  • n 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.
  • R 25 is -(CH 2 ) 3 CH ' ⁇ v
  • R 25 is -(CH 2 ) 3 C0 2 C 2 H 5 ;
  • R ⁇ is -(CH 2 ) 3 CONHC 2 H 5 ;
  • R 25 is -COCF 3 ;
  • R 25 is -PO(OC 2 H 5 ) 2 ; or a pharmaceutically acceptable salt thereof.
  • R 20 is -CO(CH 2 ) 10 CH 3 ;
  • R 20 is -COCH(p-chlorophenyl) 2 ; and (c) R 20 is -S0 2 (CH 2 ) n CH 3 ; or a pharmaceutically acceptable salt thereof.
  • X" is CI and X 1 " is OCH 3 ; or a pharmaceutically acceptable salt thereof.
  • n 1 and R 21 is CI;
  • n 2 and R 21 is OCH 3 ;
  • n is 1-4 and R 21 is OCH 3 or CI; or a pharmaceutically acceptable salt thereof.
  • R 22 is hydrogen and R 23 is CI;
  • R 22 is -C0 2 CH 3 and R 23 is -OCH 3 ; or a pharmaceutically acceptable salt thereof.
  • R 24 is CI or -OCH 3 ; or a pharmaceutically acceptable salt thereof.
  • R 26 and R 27 are both CH 3 or (C C 6 )alkyl-CF 3 ;
  • R 26 and R 27 are both CI, F or Br;
  • R 26 and R 27 are both OCH 3 or SCH 3 ;
  • R 26 is CI and R 27 is OCH 3 ;
  • R 26 and R 2 are both -COO-(C r C 6 )alkyl; or a pharmaceutically acceptable salt thereof.
  • R 25 (CH 2 )3CH 3
  • R 20 CO(CH2) ⁇ oCH 3
  • R 25 (CH2) 3 C0 2 Et
  • R 25 (CH2) 3 CONHEt
  • R 25 COC 6 H 5
  • R 25 PO(OEt) 2
  • R 22 C0 CH 3
  • R 23 OMe
  • R 4 OCH 3 and Hi
  • R 26 and R 27 are both CH 3 or -(C r C 6 )alkyl-CF 3 ;
  • R 26 and R 27 are both CI, F or Br;
  • R 26 and R 27 are both OCH 3 or SCH
  • R 26 is CI and R 27 is OCH 3 ;
  • R 26 and R 27 are both -COO-(C r C 6 )alkyl.
  • the compounds of the present invention can be prepared by various methods which are known in the art. Illustrative methods of preparation are provided in the reaction schemes which follow and in the Examples.
  • R C C ⁇ 8 alkyl
  • Scheme I shows a method of preparing compounds of general structure 6. Reaction of a phenol 2 bearing a protected carboxylate group with an alcohol 3, triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate under Mitsunobu conditions (O. Mitsunobu, Synthesis, 1, 1981) in a solvent such as tetrahydrofuran or benzene gave the ether 4.
  • the phenol 2 can be alkylated with a substituted alkyl halide (RX) and a base such as potassium carbonate in a solvent such as acetonitrile or dimethylformamide to give the ether 4.
  • the ester group of 4 is then saponified to the acid 5 by treatment with a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid.
  • a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid.
  • the acid 5 is then treated with oxalyl chloride or thionyl chloride in a solvent such as dichloromethane to give an intermediate acid chloride.
  • the acid chloride is then treated with trifluoroacetic anhydride and a base such as pyridine following conditions similar to those used by S.Z. Zard (Tetrahedron 51, 2573-2584, 1995) to give the trifluoromethyl ketone 6.
  • Scheme 2 describes a method of preparing compounds of structure 12. Reaction of an iodo-substituted phenol 7 with a dibromo alkane of structure Br(CH2)nB r the presence of a base such as potassium carbonate gives 8. The bromide 8 is then displaced with a mono or disubstituted amine in the presence of sodium iodide in a solvent such as isopropanol to give 2 or 10.
  • compound 10 can also be obtained under Mitsunobu conditions as described in Scheme 1.
  • Tertiary amines 10 are also obtained by reaction of 9 with various aldehydes RCHO by reaction with a reducing agent such as sodium cyanoborohydride in a solvent such as methanol. Similar tertiary amines 10 are also prepared by reaction of 9 with an iodo compound R(CH2) n I the presence of a base such as potassium carbonate in a solvent such as isopropanol.
  • Scheme 3 describes a method of preparing quaternary structures of type 14 and 15.
  • the tertiary amine 13 is alkylated with an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol to give the quaternary amine 14.
  • an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol
  • saponification with a base such as potassium hydroxide in a solvent such as aqueous ethanol gives the zwitterionic species 15.
  • Scheme 4 shows a method of preparing various trifluoromethyl ketones 23 from intermediates in which the trifluoromethyl ketone is protected as a ketal group.
  • the trifluoromethyl ketone 17 is prepared using the method described in Scheme 1.
  • the methyl ether 17 is then cleaved with boron tribromide in a solvent such as dichloromethane to give the phenol IS.
  • the ketone group is then protected as a ketal 19 by reaction with an orthoester such as trimethyl orthoformate catalyzed by an acid such as trifluoromethanesulfonic acid and in solvents such as nitromethane and methanol.
  • the phenol 19 is then treated as described for Z in Scheme 2 to give 2Q, 21 and 22-
  • the protected trifluoromethyl ketone in 22 allows various modifications on R such as reduction of an ester group with lithium aluminum hydride or diisobutyl aluminum hydride.
  • the ketal group is then cleaved with an acid such as trifluoroacetic acid to give 23.
  • Scheme 5 describes preparation of tertiary amines by alkylation of intermediate 21 obtained in Scheme 4 by reaction with an alkyl iodide such as iodopropane in a solvent such as isopropanol and in the presence of a hindered base such as N,N-diisopropylethylamine.
  • the ketal 24 is then cleaved as described in Scheme 4 to give the trifluoromethyl ketone 25.
  • Scheme 6 describes preparation of a variety of trifluoromethyl ketones 27 starting from the phenol 19 obtained in Scheme 4. Reaction of 19 with various alcohols of structure ROH under the Mitsunobu conditions described in Scheme 1 gave 26. Deprotection of the ketal group as described in Scheme 4 gives 27 possessing a variety of ether substituents.
  • Scheme 7 shows a synthetic route to acylated or sulfonylated amines 33.
  • Reaction of 4-hydroxybenzaldehyde with a t-butoxycarbonyl- protected amino-alcohol such as 29 under Mitsunobu conditions similar to those described in Scheme 1 gives the aldehyde 3_Q.
  • amide 33 is then acylated with various acyl chlorides such as palmitoyl chloride under Schotten- Baumann conditions in a mixture of solvents such as tetrahydrofuran and saturated aqueous sodium acetate to give amide 33.
  • the amine trifluoroacetate salt can be treated with an alkylsulfonyl chloride such as 1-heptanesulfonyl chloride or an alkyl isothiocyanate such as N- decyl isothiocyanate in presence of a base such as triethylamine and in a solvent such as dichloromethane to give a sulfonamide or a thiourea respectively.
  • Scheme S describes a method of preparing amides of structure 39 which are regioisomers of structures described in Scheme 7.
  • 4- Hydroxybenzaldehyde was treated with 1,1,1-trifluoroacetone as described in Scheme 7 and alkylated with a bromoester such as t-butyl bromoacetate in the presence of a base such as potassium carbonate and in a solvent such as acetone to give 36.
  • a base such as potassium carbonate
  • a solvent such as acetone
  • 36 can be obtained via the same sequence of steps but in inverse order.
  • the phenol 34 can also be acylated with various acid chlorides such as a palmitoyl chloride to give ester derivatives such as 36b.
  • the t-butyl protecting group of 36 is then cleaved with an acid such as trifluoroacetic acid in dichloromethane to give the acid 3_Z.
  • This acid is then reacted with primary and secondary amines such as dodecylamine in the presence of a condensing agent such as N- ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline (EEDQ) to give the amide 3S.
  • EEDQ N- ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline
  • Reduction and oxidation of the enone as described in Scheme 7 gave the amide 39.
  • the enone 36 can be reduced first to 40 and then cleaved as above to the acid 41.
  • Scheme 9 describes a method for making compounds of structure 46. 47 and 48 which contain a sulfur atom.
  • Reaction of an alcohol 43. which contains a sulfur atom, usually obtained by reaction of a thiol with a halogen-substituted alcohol, with phenol 42 under Mitsunobu conditions as described in Scheme 1 gives the ether 44- Preparation of the trifluoromethylketone 46 is then achieved via the two-step sequence also described in Scheme L
  • Oxidation of 4j5 with a peracid such as m- chloroperbenzoic acid gives the sulfone 47.
  • Oxidation of 46 with sodium periodate in a mixture of methanol and water affords the sulfoxide 48.
  • 3 H-arachidonate-labeled U937 membranes were prepared from U937 cells grown in RPMI 1640 medium containing L-glutamine supplemented with 10% fetal calf serum and 50 ⁇ g/ml gentamycin in a 5% C0 2 incubator at 37°C. Sixteen hours prior to harvesting the cells, 3 H- arachidonate (100 Ci/mmol) was added to the cell culture (lxlO 6 cells/ml, 0.5 ⁇ Ci/ml).
  • HBSS Human Serum Albumin
  • HSA Human Serum Albumin
  • Assays of cPLA 2 activity using these 3 H-arachidonate-labeled U937 membranes as substrate typically employ human recombinant cPLA 2 (see Burke et al., Biochemistry 34: 15165-15174, 1995) and membrane substrate (22 ⁇ m phospholipid) in 20 mm HEPES [N-(2-hydroxyethyl) ⁇ iperazine-N 1 - (2-ethanesulfonic acid)] buffer, pH 8, containing 6 mm CaCl 2 , 0.9 mg/ml albumin and 4 m glycerol. Enzyme assays are allowed to proceed for 3 hours at 37°C before removing the non-hydrolyzed membranes. The hydrolyzed, radiolabeled fatty acid is then measured by liquid scintillation counting of the aqueous phase.
  • inhibitor is calculated as percent inhibition of 3 H- arachidonate formation, after correcting for nonenzymatic hydrolysis, as compared to a control lacking inhibitor according to the following formula:
  • the compounds of the present invention are selective inhibitors of cytosolic phospholipase A 2 , they are of value in the treatment of a wide variety of clinical conditions.
  • Inflammatory disorders which may be treated by inhibition of cytosolic cPLA 2 include such conditions as arthritis, psoriasis, asthma, inflammatory bowel disease, gout, trauma-induced inflammation such as spinal cord injury, Alzheimer's Disease, cerebral ischemia, chronic skin inflammation, shock, damage to skin resulting from exposure to ultraviolet light or burns, allergic rhinitis, acute pancreatitis, and the like.
  • the compounds of formula I are usually administered in the form of pharmaceutical compositions. They can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound defined by formula I and a pharmaceutically acceptable carrier.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • the hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (IM) in ether.
  • IM anhydrous hydrochloric acid
  • the hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (IM) in ether.
  • IM anhydrous hydrochloric acid
  • the hydrochloride was obtained as a syrup.
  • Ethyl bromoacetate (3.0 g, 18.0 mmol) was added dropwise to a boiling solution of zinc powder (1.7 g, 26.0 at g) and iodine (30.0 mg) in dichloromethane (5 ml) to form the Reformatsky reagent (K. Bott, Tetrahedron Lett., 1984, 35, 555-556).
  • the mixture was then cooled to 0°C and treated dropwise with a solution of 4,4'-dichlorobenzhydryl chloride (5.11 g, 15.8 mmol) in dichloromethane (10 ml) and the resulting mixture was stirred at 22°C for 3 h.
  • N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy] ethyl] dodecylamine (353mg, 0.63mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester .
  • the residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 94 : 6) to afford the title compound (253mg, 78%) as a pale yellow oil.
  • N-Ethyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy]ethyl]dodecylamine (123mg, 0.244mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (60mg, 54%) as a pale yellow oil.

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JP2019182867A (ja) * 2011-10-27 2019-10-24 Massachusetts Institute Of Technology 薬物内包微小球の形成が可能なｎ−末端で官能基化されたアミノ酸誘導体
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CA2304503A1 (en) 1999-04-01
US6255496B1 (en) 2001-07-03
WO1999015129A3 (en) 2001-07-26
AU730364B2 (en) 2001-03-08
EP1140791A2 (de) 2001-10-10
PE122999A1 (es) 2000-02-17
AU9395498A (en) 1999-04-12
CO4970751A1 (es) 2000-11-07

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